Mayo was born in Hampton, Virginia. He attended Kecoughtan High School in Hampton, where he earned three letters in football as a linebacker and a running back. As a senior, Mayo recorded 110 tackles, including 18 for loss, and two interceptions. Also playing running back for seven games, he picked up 1,245 rushing yards and scored 13 touchdowns and five two-point conversions during his final campaign. As a junior, he recorded 68 tackles including 22 for loss, four interceptions and three sacks and earned first-team All-District, All-Area and All-Region honors.

While attending the University of Tennessee, Mayo played for the Tennessee Volunteers football team from 2004 to 2007.[2] After redshirting the 2004 season, he appeared in six games at weak-side outside linebacker in 2005, finishing with 13 tackles (10 solo). Mayo made the Volunteers starting lineup as a redshirt sophomore in 2006, as he started 11 contests at weak-side outside linebacker. He finished third on the team with 83 tackles (48 solos), including five sacks for minus 40 yards, 12.5 stops for losses of 51 yards and a quarterback pressure. He also recovered one fumble and deflected a pass. Rivals.com subsequently named him to their All-American second team.[2]

For his junior season, Mayo moved to middle linebacker and started all 14 games. Serving as the defensive squad's co-captain, he went on to register 140 tackles in 2007, the most by a Tennessee defender since Earnest Fields registered those same totals for the Volunteers in 1990. He added 1.5 quarterback sacks for minus 11 yards, 8.5 stops for losses and five quarterback pressures, and also returned an interception 34 yards for a touchdown. Mayo was a first-team All-Southeastern Conference selection and also earned All-American second-team honors by The NFL Draft Report.[2]

Mayo was considered one of the best linebackers available in the 2008 NFL Draft and drew comparisons to Will Witherspoon.[3]Sporting News described Mayo as a “perfect fit to play one of the inside spots” in a 3-4 defense.

Mayo was drafted by the New England Patriots with the tenth overall pick in the 2008 NFL Draft. He was signed on July 24, 2008, to a five-year contract (rather than the six-year maximum allowed by the NFL's collective bargaining agreement) worth $18.9 million, including $13.8 million in bonuses and guarantees.[4] Mayo was the only rookie in the Patriots' 2008 class to start in Week 1, and played every snap for the defense.[5]

Mayo was named the NFL's Defensive Rookie of the Month for October 2008.[6] He led the Patriots with 24 tackles for the month, including 11 against the Denver Broncos in his first Monday Night Football appearance. In the Patriots' Thursday Night Football game on November 13, 2008, against their division rivals, the New York Jets, Mayo led all defensive players with 20 tackles (16 solo, 4 assisted), the first 20-tackle game of his career.

Mayo was injured in the Patriots' 2009 season opener against the Buffalo Bills. The sprained MCL in his knee was originally expected to keep him out 6–8 weeks,[8] but he returned in Week 5 against the Denver Broncos. Mayo finished the season with 103 tackles and 1.5 sacks.[6]

In 2010, Mayo was named a defensive captain.[9] In Week 4 against the Miami Dolphins, Mayo recorded 16 tackles, and two weeks later notched 18 tackles in an overtime win over the Baltimore Ravens. In Week 8, Mayo recorded 14 tackles in a win over the Minnesota Vikings. Against the Indianapolis Colts in Week 11, Mayo recorded 15 tackles in a win. In Week 12, Mayo's eight tackles gave him 132 on the season, surpassing his previous career high of 128, set in 2008. He added another 12 tackles in Week 13 against the New York Jets, and had 16 in Week 15 against the Green Bay Packers. He ended the season with a league-high 175 tackles, along with two sacks and one forced fumble.

He was named as a reserve to the 2011 Pro Bowl on January 2, 2011. In the same season he was named to the 2010 All Pro team.[6]

On December 17, 2011 at the beginning of Week 15 it was announced that he had signed a 5-year contract extension.[10]

In 2011, he missed 3 games due to injuries but still managed to eclipse the 100 tackle mark. Mayo and the Patriots reached Super Bowl XLVI. Mayo had 11 tackles but the Patriots lost to the New York Giants 21-17.[6]

Mayo has a well known work ethic that is derived from his reputation as a player who shows up early, stays late, watches film, practices hard and puts himself through intense work outs in the team’s weight room.[14] Mayo’s positive attitude was highlighted in Michael Holley’s book “War Room”

”Mayo had been a top ten pick who didn’t act like one. On draft day, when the best of the best are invited to New York, often wearing made-for-occasion tailored suits, Mayo had been home in Virginia with his family raking leaves. He was a worker there and a worker in Foxboro. In the off season, he’d come to the stadium and watch film, even when there were no coaches to be found. He loved the game, and it could be seen by the way he played middle linebacker, never turning down the opportunity to plug a hole or run sideline to sideline.”[15]

Mayo has two brothers both of whom played college football. His brother Deron Mayo plays in the Canadian Football League,[18] and his brother Derek Mayo is a graduate of Richmond. Jerod, Deron and Derek Mayo are all linebackers. Derek's Richmond team won the NCAA Football Championship Subdivision title in 2008.

Mayo has been involved with United Way, filming a PSA for the New Hampshire 2-1-1 help line. In 2010 Jerod and Chantel Mayo organized an inaugural celebrity bowling tournament at Kings Dedham at Legacy Place. The annual event benefited Pitching in for Kids, Inc., a nonprofit organization dedicated to providing earmarked grants that improve the lives of children in New England.